The mechanisms underlying human immunodeficiency virus (HIV)-mediated cell death in the central nervous system (CMS) are not well defined, but evidence suggests that oxidative stress plays a critical role in neuropathogenesis in HIV-associated dementia (HAD). Several mouse models of HAD have been developed, but few are suitable to the study of oxidative stress and cell death pathways in HAD. In our model of HAD, FVB/N mice are infected with a mutant of the Moloney murine leukemia virus, called te1, which causes progressive neuroimmunodegeneration that is in many ways similar to that of HAD. As in HAD, glial cells are infected by te1, but neurons are not, although neuronal loss is the most severe pathological feature in the CMS. Work in our lab has focused on the role of oxidative stress in the death of te1 -infected astrocytes, and on prevention of neurodegeneration (ND) via antioxidant treatment. We hypothesize that te1 -mediated oxidative stress causes astrocyte dysfunction, that dysfunctional astrocytes are unable to support nearby neurons, and that neurons die as a result. In support of this idea, we have demonstrated that reactive oxygen species (ROS) accumulate in te1-infected astrocytes. Treatment with an antioxidant called GVT (a-luminol) decreases ROS accumulation and prevents cell death in te1-infected astrocytes and in CNS of te1-infected mice. We have also shown that p53 phosphorylation occurs in astrocytes and neurons of te1 -infected mice, and that death of these cells may involve activation of p53-dependent cell death pathways. Further, te1- infected astrocytes respond to ROS increases via activation of ataxia telangiectasia mutated (ATM), extracellular signal-regulated kinases (ERK), and mammalian target of rapamycin (mTOR). All these three kinases have been shown to be able to phosphorylate p53. In te1 -infected astrocytes, the p53-target proapoptotic factors PUMA, Bax, and cell cycle inhibitor p21 are upregulated, and the antiapoptotic factors Bcl-2 and Bcl-xL decrease. All of these events are known to occur in HAD. We hypothesize that similar cell death mechanisms contribute to te1 -associated ND and HAD. Our goal is therefore to understand the mechanisms underlying astrocyte dysfunction and neuronal death in te1 -mediated ND. We will focus on three specific aims: 1) to determine how p53 contributes to oxidative stress;2) to confirm that neurons are damaged by oxidative stress through pathways shared by astrocytes;and 3) to determine whether antioxidants and thiol-repleting agents provide protection for astrocytes and neurons. Our studies may identify new targets for treatment of HAD and of other neurodegenerative diseases associated with oxidative stress, p53 activation and the mitochondrial death pathway.